Date of Award

12-2008

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

Yisong Wang

Committee Members

Brynn Voy, Hayes McDonald, Bruce Mckee, Sundar Venkatachalam

Abstract

Centrosomes are the only non-membranous organelles in most vertebrate cells and their major function is to nucleate microtubules, hence often recognized as the microtubule-organizing center (MTOC). Much like chromosome centrosome duplicates only once during the S phase of each cell cycle. The fidelity and timing of this duplication event will ensure equal division of duplicated chromosomes into the daughter cells. As a consequence, numerical and/or structural centrosome abnormalities will cause chromosome missegregation and lead to the generation of multiple mitosis and ultimately chromosomal instability, which typify many cancers.

The molecular mechanism of centrosome duplication remains unclear. Previous studies found that a fraction of human proline-directed phosphatase Cdc14B associates with centrosomes. However, Cdc14B’s involvement in centrosome cycle control has never been explored. In this study, we identify Cdc14B as a negative regulator in centrosome cycle control: depletion of Cdc14B by RNA interference leads to centriole amplification in both HeLa and normal human fibroblast BJ and MRC-5 cells; ectopic expression of Cdc14B leads to stepwise loss of centrioles and attenuates centriole amplification in HU/APH arrested S phase cells and cells treated with proteasome inhibitor Z-L3VS. This inhibitory function requires centriole-associated Cdc14B catalytic activity. In addition, our data suggests counterbalancing effects between Cdc14B phosphatase and kinases such as Plk4, Cdk2/Cyclin-E/A in centrosome duplication control potentially through modulating phosphorylation status of their common downstream effectors, HsSas-6 and B23 respectively. Taken together, these results suggest a potential function for Cdc14B phosphatase in maintaining the fidelity of centrosome duplication cycle.

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